Identification of a Venetoclax-resistance Prognostic Signature Base on 6-senescence Genes and Its Clinical Significance for Acute Myeloid Leukemia

Overview

Journal Front Oncol

Specialty Oncology

Date 2023 Dec 15

PMID 38098504

Authors

Peng Ke

Jundan Xie

Ting Xu

Meiyu Chen

YuSha Guo

Ying Wang

Huiying Qiu

Depei Wu

Zhao Zeng

Suning Chen

Xiebing Bao

Affiliations

Soon will be listed here.

Abstract

Background: Satisfactory responses can be obtained for acute myeloid leukemia (AML) treated by Venetoclax (VEN)-based therapy. However, there are still quite a few AML patients (AMLs) resistant to VEN, and it is critical to understand whether VEN-resistance is regulated by senescence.

Methods: Here, we established and validated a signature for predicting AML prognosis based on VEN resistance-related senescence genes (VRSGs). In this study, 51 senescence genes were identified with VEN-resistance in AML. Using LASSO algorithms and multiple AML cohorts, a VEN-resistance senescence prognostic model (VRSP-M) was developed and validated based on 6-senescence genes.

Results: According to the median score of the signature, AMLs were classified into two subtypes. A worse prognosis and more adverse features occurred in the high-risk subtype, including older patients, non- AML, poor cytogenetics, adverse risk of European LeukemiaNet (ELN) 2017 recommendation, and mutation. Patients in the high-risk subtype were mainly involved in monocyte differentiation, senescence, NADPH oxidases, and PD1 signaling pathway. The model's risk score was significantly associated with VEN-resistance, immune features, and immunotherapy response in AML. , the IC50 values of ABT-199 (VEN) rose progressively with increasing expression of and in AML cell lines.

Conclusions: The 6-senescence genes prognostic model has significant meaning for the prediction of VEN-resistance, guiding personalized molecularly targeted therapies, and improving AML prognosis.

Citing Articles

Paired comparisons of venetoclax concentration in cerebrospinal fluid, bone marrow, and plasma in acute leukemia patients.

Jian Y, Han F, Zhu Y, Geng C, Zhang Y, Wu Y Clin Transl Sci. 2024; 17(9):e70006.

PMID: 39286959 PMC: 11406145. DOI: 10.1111/cts.70006.

Monocytic Differentiation in Acute Myeloid Leukemia Cells: Diagnostic Criteria, Biological Heterogeneity, Mitochondrial Metabolism, Resistance to and Induction by Targeted Therapies.

Bruserud O, Selheim F, Hernandez-Valladares M, Reikvam H Int J Mol Sci. 2024; 25(12).

PMID: 38928061 PMC: 11203697. DOI: 10.3390/ijms25126356.

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